In 2015 over half a million Americans ages 12 and older were regular inhalant users. Inhalant use can result in profound neurological and organ damage and use is correlated with mental health treatment, delinquent behaviors and the abuse of other drugs. Despite the scope of the problem inhalants are the most poorly understood and chronically understudied of all the major classes of abused drugs, a problem exacerbated by a lack of resources, relevant technical expertise and validated methods. While our understanding of the effects of a few highly abused inhalants such as toluene has slowly advanced despite the difficulties, emerging inhalant threats have been almost completely unexplored. This is especially true with regard to the abuse of chlorocarbon gases. ?Dusting? as abuse of chlorocarbon gas products is referred, has contributed to a large number of well-publicized deaths due directly to the product effects or as a result of reckless behaviors while under the influence of the product. Alarmingly, chlorocarbon abuse may be supplanting abuse of other inhalants in the U.S., especially in adults, perhaps due to the perception of decreased risk or the fact that unlike other inhalants with strong odors, dusters have no lingering indications of use. The overarching goal of this R21 Developmental/Exploratory grant is to determine the extent to which two of the most commonly available chlorocarbons 1,1,1,2-tetrafluoroethane (R134a) and chloroethane engender abuse-related behaviors. We will accomplish this goal through two aims conducted in mice. Aim 1 will use male and female mice to assess the effects of each chlorocarbon on acute locomotor activity as well as if repeated administration induces locomotor sensitization. Sensitization is a phenomenon whereby the initial effect of a drug is enhanced following repeated administration and a characteristic of many drugs of abuse. We believe the demonstration of sensitization resulting from chlorocarbon exposure would provide a strong rationale for more detailed studies on the effects of these compounds on abuse-related neurocircuitry. Aim 2 will examine if chlorocarbons will facilitate intracranial self-stimulation behavior, demonstrating the extent to which chlorocarbon gases positively modulate brain reward mechanisms. Further, by comparing ICSS facilitation produced by chlorocarbons to that of toluene, arguably the most frequently abused inhalant, we believe it will be possible to ascertain the relative abuse liability of these chemicals. To maximize the potential to make predictions and the translational value of our data we will use both male and female subjects and have designed out studies to explore the impact of each of the chlorocarbon gases across estrous cycle phase. Taken as a whole this exploratory/developmental analysis will provide the critical foundation necessary for more detailed experiments aimed at understanding the neurochemistry underlying the abuse-related effects of chlorocarbon dusters.